Impact of the Addition of a Centrifugal Pump in a Preterm Miniature Pig Model of the Artificial Placenta.

The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit (n = 12; 98 ± 4 days; 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.

Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus.

Artificial placenta (AP) technology aims to maintain fetal circulation, while promoting the physiologic development of organs. Recent reports of experiments performed in sheep indicate the intrauterine environment can be recreated through the cannulation of umbilical vessels, replacement of the placenta with a low-resistance membrane oxygenator, and incubation of the fetus in fluid. However, it remains to be seen whether animal fetuses similar in size to the extremely preterm human infant that have been proposed as a potential target for this technology can be supported in this way. Preterm Yucatan miniature piglets are similar in size to extremely preterm human infants and share similar umbilical cord anatomy, raising the possibility to serve as a good model to investigate the AP. To characterize fetal cardiovascular physiology, the carotid artery (n = 24) was cannulated in utero and umbilical vein (UV) and umbilical artery were sampled. Fetal UV flow was measured by MRI (n = 16). Piglets were delivered at 98 ± 4 days gestation (term = 115 days), cannulated, and supported on the AP (n = 12) for 684 ± 228 min (range 195-3077 min). UV flow was subphysiologic (p = .002), while heart rate was elevated on the AP compared with in utero controls (p = .0007). We observed an inverse relationship between heart rate and UV flow (r2  = .4527; p < .001) with progressive right ventricular enlargement that was associated with reduced contractility and ultimately hydrops and circulatory collapse. We attribute this to excessive afterload imposed by supraphysiologic circuit resistance and augmented sympathetic activity. We conclude that short-term support of the preterm piglet on the AP is feasible, although we have not been able to attain normal fetal physiology. In the future, we propose to investigate the feasibility of an AP circuit that incorporates a centrifugal pump in our miniature pig model.

Association Between Cyanosis, Transfusion, and Thrombotic Complications in Neonates and Children Undergoing Cardiac Surgery.

OBJECTIVE: Children with congenital heart defects are at increased risk for perioperative bleeding and postoperative thrombosis. In this study, the authors sought to develop a predictive model for postoperative thrombotic complications that integrates intraoperative bleeding and the requirement for allogenic blood products in addition to known patient and surgical characteristics. DESIGN: Retrospective cohort. SETTING: Pediatric hospital. PARTICIPANTS: Neonates and children who underwent surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Demographic, laboratory, point-of-care coagulation, surgical, and perioperative transfusion data were collected. Among the 369 participants included in the study, 67 (18%) developed postoperative thrombotic complications. From multivariable logistic regression analyses, preoperative oxygen saturation <85% (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.10-3.85; p = 0.024), surgery in the neonatal period (OR 2.16, 95% CI 1.02-4.55; p = 0.044), use of preoperative antiplatelet or anticoagulation therapy (OR 3.34, 95% CI 1.61-6.96; p = 0.001), and the volume of blood product transfused post-CPB (>80 mL/kg [OR 5.72, 95% CI 1.73-18.91; p = 0.004] and 15-80 mL/kg [OR 3.06, 95% CI 1.24-7.53; p = 0.015]) were independently associated with an increased incidence of thrombotic complications. No statistical differences were observed in available preoperative coagulation tests between children who developed postoperative thrombosis and those who did not. CONCLUSION: This observational cohort study found that cyanosis, surgery in neonates, preoperative anticoagulation or antiplatelet therapy, and the volume of post-CPB transfusion are important predictors of postoperative thrombotic complications in children undergoing cardiac surgery. Additional studies are required to explore the relationship between hypoxia, coagulopathy, and postoperative thrombosis.

Predicting Heparin Responsiveness in Children Before Cardiopulmonary Bypass: A Retrospective Cohort Study.

BACKGROUND: Inadequate or excess administration of unfractionated heparin for cardiopulmonary bypass (CPB) can cause significant harm. Age-dependent differences in the pharmacodynamics and pharmacokinetics of heparin contribute to increased variability of heparin responsiveness in children. The aims of the current study were to (1) examine the correlation between predicted and observed heparin responsiveness in children before CPB measured using the Hemostasis Management System (HMS) Plus (Medtronic, Minneapolis, MN), (2) describe age-specific reference intervals for heparin sensitivity index (HSI) observed in children, and (3) test predictive models of HSI using preoperative clinical and laboratory data. METHODS: In this retrospective cohort study, children (ages ≤17 years) who required therapeutic heparinization for CPB in a 40-month period between September 2010 and December 2013 were investigated. Children weighing ≥45 kg or with a height ≥142 cm were excluded. HSI was defined as the difference between activated clotting time after heparin administration and the baseline activated clotting time divided by the heparin-loading dose (IU) per kilogram. Lin's concordance correlation coefficient was used for the primary analysis of the relationship between predicted and observed HSI. Reference intervals were calculated for HSI using medians and 2.5% and 97.5% percentiles according to established guidelines for clinical and laboratory standards. Nonparametric regression analyses were used to model the relationship between HSI (dependent variable) and preoperative covariates (independent variables). RESULTS: A total of 1281 eligible children were included in the final analysis. Overall, there was a moderate correlation between predicted and observed HSI measured using HMS Plus System (rho_c = 0.46; 95% confidence interval, 0.41-0.50; P < .001). Sixty-five percent (829 of 1281) of predicted HSI values were less than observed. From adjusted regression models, HSI was best predicted by preoperative international normalized ratio, platelet count, and weight, but this model accounted for only 25% of the variance in HSI. CONCLUSIONS: In a large cohort of children, heparin responsiveness before CPB was not reliably predicted by either in vitro measurement using the HMS Plus System or commonly available preoperative clinical and laboratory data. We describe age-specific reference intervals for HSI in children, and we anticipate that these data will aid the identification of heparin resistance in this population.

Novel Leg Cannula for Venous Decompression in Peripheral Extracorporeal Membrane Oxygenation.

A chimney femoral artery graft for peripheral extracorporeal membrane oxygenation can potentially cause hyperperfusion and subsequent venous congestion in the ipsilateral leg, especially in the context of septic shock and higher flow requirement. This report describes a novel technique to use an additional leg venous cannula to avoid leg congestion as well as to achieve higher total flow.

The Association Between Cyanosis and Thromboelastometry (ROTEM) in Children With Congenital Heart Defects: A Retrospective Cohort Study.

BACKGROUND: Children with congenital heart defects (CHD) have quantitative and qualitative differences in coagulation compared with healthy children. Secondary to polycythemia and increased deformability of red blood cells, cyanosis may be an important confounding factor for altered whole-blood coagulation in this population with potential implications for interpreting intraoperative thromboelastometry (TEM) for children with CHD undergoing major surgery. The primary aim of the study was to evaluate the association between cyanosis in children with CHD and measures of whole-blood coagulation determined using TEM (ROTEM [Tem International, GmbH, Munich, Germany]). METHODS: In this retrospective cohort study, children who underwent congenital cardiac surgery in a 12-month period between April 2014 and 2015 were investigated. Children who were receiving antiplatelet or anticoagulant medications in the preoperative period were excluded. Eligible children were categorized by the presence of cyanosis, defined as an oxyhemoglobin concentration ≤85%. Multivariable linear regression analyses were used to determine the relationship between cyanosis and TEM outcomes (primary outcome, fibrinogen/fibrin polymerization [FibTEM] maximal clot firmness [MCF]) adjusting for potential confounding factors. RESULTS: Three hundred forty-five TEM profiles from 320 children were included in the cohort for analysis. Twenty-two percent (76/345) of children had cyanotic CHD. Clot firmness measured using the FibTEM assay was decreased in cyanotic children compared with noncyanotic children, median difference (95% confidence interval) interim [2 (0-3) mm; P = .01], and maximal [2 (1-3) mm; P = .01] clot firmness. The association between cyanosis and fibrinogen/fibrin polymerization clot firmness was not significant (A10, P = .7; MCF, P = .7) after adjusting for confounding factors (hematocrit, platelet count, and sex). There was a significant association between cyanosis and intrinsically activated clot firmness (A10, P = .03; MCF, P = .02), but not other TEM outcomes, after adjusting for confounding factors. CONCLUSIONS: Cyanotic children had decreased clot firmness in the fibrinogen/fibrin polymerization component of the clot compared with noncyanotic children, but the association between cyanosis and clot firmness was accounted for by differences in hematocrit, platelet count, and sex between groups. These findings will help guide the identification and treatment of coagulopathy in this vulnerable population.

Cavopulmonary support with a microaxial pump for the failing Fontan physiology.

The number of patients with the failing Fontan physiology is increasing. We tested a novel in situ microaxial pump (Impella) to support the failing atrio-pulmonary Fontan circulation in an acute pig model. A Fontan model was established in eight juvenile pigs by connecting the right atrium to the main pulmonary artery after tricuspid valve destruction. The Impella pump was inserted retrograde from the distal main pulmonary artery into the right atrium. Hemodynamics, blood gas, and echocardiographic data were compared among baseline, pure Fontan physiology (10 minutes), and mechanically assisted Fontan physiology (up to 12 hours). The Impella system generated a blood flow of 75-85 ml/kg/minute in six animals, and 55-65 ml/kg/minute in two animals. The mechanically assisted Fontan attained a significantly higher mean blood pressure (39.6 ± 7 vs. 24.7 ± 3.3 mm Hg, p < 0.01), lower central venous pressure (5 ± 2.4 vs. 12.8 ± 1.7 mm Hg, p < 0.01), and higher mixed venous saturation (60.4 ± 10.8 vs. 23.4 ± 8.4 mm Hg, p < 0.01) compared with pure Fontan physiology. Cardiac output and stroke volume were similar during baseline and mechanically assisted Fontan (p = not significant). This acute pig study demonstrated the feasibility of mechanical circulatory support in the failing Fontan physiology. The in situ microaxial pump maintained cardiac output while increasing blood pressure and reducing venous pressure.

Heparin brand is associated with postsurgical outcomes in children undergoing cardiac surgery.

BACKGROUND: We sought to determine whether the use of specific unfractionated heparin brands during cardiopulmonary bypass for pediatric cardiac surgery was associated with differences in postoperative outcomes, especially regarding the incidence of bleeding and thromboembolic complications. METHODS: We compared postoperative outcomes for pediatric cardiac surgeries performed with Hepalean (Organon Teknika) to those performed with PPC heparin (Pharmaceutical Partners of Canada). Differences in clinical outcomes were determined in multivariable logistic and linear regression models adjusted for patients and surgery characteristics. RESULTS: In all, 903 operations were reviewed, 289 (32%) using Hepalean and 614 (68%) using PPC heparin. Patient demographics and surgical variables were comparable between groups. In multivariable regression models, adjusted for patients' characteristics, heparin use and choice of antifibrinolytic agents, the use of PPC heparin was associated with greater use of red blood cell transfusions in the first 48 postoperative hours (estimates +1.6 mL/kg, p<0.001), increased odds of bleeding complications (odds ratio 3.8, p=0.04), thromboembolic complications (odds ratio 4.7, p=0.01), early unplanned reoperation (odds ratio 6.9, p=0.03), longer postoperative intensive care unit stay (estimate +3.2 days, p<0.001), and longer hospital stay (estimate +3.6 days, p<0.001). CONCLUSIONS: Brand of unfractionated heparin used during cardiopulmonary bypass for pediatric cardiac surgery was associated with bleeding complications and clinical outcomes. Different brands of unfractionated heparin should not be considered equivalent without proper validation in formal trials.

Longer blood storage is associated with suboptimal outcomes in high-risk pediatric cardiac surgery.

BACKGROUND: The negative effects of long-term storage of allogeneic red blood cells (RBCs) on outcomes in adult cardiac surgery have been established, but evidence of a similar effect in pediatric cardiac surgery is limited. METHODS: The weighted average duration of storage for RBC units used in 1,225 pediatric cardiac operations was determined. Operations were divided into high RBC use (more than 4 units or more than 150 mL/kg) or low RBC use. For both categories, associations between storage duration and surgical outcomes, adjusted for relevant patient characteristics, were evaluated. RESULTS: High RBC use was associated with higher surgical complexity. Storage duration for patients who received low RBC volumes was not associated with surgical outcomes. For patients with high RBC transfusion volumes, longer storage duration (per day) was associated with higher odds of bleeding complications (odds ratio 1.029, p=0.07), renal insufficiency (odds ratio 1.085, p=0.001), higher inotrope score after surgery (12 to 24 hours +0.08, p=0.002; 24 to 48 hours +0.07, p<0.001), greater chest tube drainage (24 hours +1.5 mL/kg, p<0.001), longer postoperative hospitalization (+0.3 days p=0.02), and increased in-hospital mortality (odds ratio 1.054, p=0.03). Effects of RBC transfusions on postoperative bleeding were greatest for storage duration longer than 14 days. CONCLUSIONS: The freshest RBC units available should be used for pediatric cardiac operations expected to require more than 4 units or more than 150 mL/kg of allogeneic RBC transfusions, with no units more than 14 days old being transfused whenever possible.

Randomized, controlled trial of individualized heparin and protamine management in infants undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVES: We sought to determine whether infants (younger than 1 year old) had similar clinical benefits with individualized anticoagulation management as older children and adult undergoing cardiopulmonary bypass (CPB). BACKGROUND: Individualized heparin and protamine management in older children and adults undergoing CPB has been associated with improved clinical outcomes. METHODS: Ninety infants younger than 1 year of age undergoing CPB were enrolled in a randomized, controlled trial comparing weight-based anticoagulation management using activated clotting time (ACT) to individualized management with Hemostasis Management System Plus. Manufacturer's guidelines were followed for the first 33 patients. A modified protocol was used for the last 57 patients with adjustments for coagulation system immaturity and hemodilution on CPB. RESULTS: The hemostasis management system (HMS) device consistently underestimated plasma anti-Xa levels, leading to an overestimated required heparin dose. After a blinded interim analysis revealed poor outcomes in the experimental HMS group using manufacturer guidelines, the safety committee suspended the study pending protocol modifications. The use of the HMS device following the modified protocol resulted in more stable anti-Xa levels during CPB with improved post-operative outcomes including reduced need for transfusions (71 ml/kg vs. 80 ml/kg; p = 0.003), ventilation time (33 h vs. 49 h; p = 0.04), intensive care (88 h vs. 99 h; p = 0.003), and hospital length of stay (192 h vs. 216 h; p < 0.001), compared with the weight-based protocol. CONCLUSIONS: This study supports the use of the HMS device, with a modified protocol for infants younger than 1 year of age, for anticoagulation management during CPB. Clinical guidelines for the use of the HMS device should be modified for infants younger than 1 year of age.

Management and monitoring of anticoagulation for children undergoing cardiopulmonary bypass in cardiac surgery.

Cardiopulmonary bypass (CPB) creates a pro-coagulant state by causing platelet activation and inflammation leading to thrombin generation and platelet dysfunction. It is associated with severe derangements in normal homeostasis resulting in both thrombotic and hemorrhagic complications. This derangement is greater in children with congenital heart disease than in adults because of the immaturity of the coagulation system, hemodilution of coagulation factors, hyperreactive platelets, and in some patients, physiologic changes associated with cyanosis. During CPB, an appropriate amount of heparin is given with the goal of minimizing the risk of thrombosis and platelet activation and at the same time reducing the risk of bleeding from over anticoagulation. In young children, this balance is more difficult to achieve because of inherent characteristics of the hemostatic system in these patients. Historically, protocols for heparin dosing and monitoring in children have been adapted from adult protocols without re-validation for children. Extreme hemodilution of coagulation factors and platelets in young children affects the accuracy of anticoagulation monitoring in children. The activated clotting time does not correlate with plasma levels of heparin. In addition, recent studies suggest that children need larger doses of heparin than adults, because they have lower antithrombin levels, and they metabolize heparin more rapidly. Preliminary studies demonstrated that the use of individualized heparin and protamine monitoring and management in children is associated with reduced platelet activation and dysfunction and improved clinical outcomes. However, this review article clearly establishes that further studies are necessary to obtain evidence-based protocols for the proper management of anticoagulation of children undergoing cardiopulmonary bypass.

Survival outcomes after rescue extracorporeal cardiopulmonary resuscitation in pediatric patients with refractory cardiac arrest.

OBJECTIVES: We report our experience with extracorporeal cardiopulmonary resuscitation with extracorporeal membrane oxygenation in children having cardiac arrest refractory to conventional cardiopulmonary resuscitation and explore predictors for favorable outcome (survival with grossly intact neurologic status). METHODS: We reviewed all patients who required extracorporeal cardiopulmonary resuscitation from 2000 to 2005. Multivariable regression analysis determined factors associated with favorable outcome and time-related survival. RESULTS: Eighty children, median age 150 days (range: 1 day-17.6 years), required venoarterial extracorporeal cardiopulmonary resuscitation. There were several categories of disease among the patients: postcardiotomy (n = 39), unoperated congenital heart disease (n = 17), cardiomyopathy (n = 12), respiratory failure (n = 9), or myocarditis (n = 3). Cannulation sites were neck (n = 45) or chest (n = 36). Median duration of extracorporeal membrane oxygenation was 4 days (range: 1-22). Extracorporeal membrane oxygenation was successfully discontinued in 42 (54%) patients: wean (n = 35), heart transplantation (n = 7). Survival till hospital discharge was 27 (34%) patients. Most common cause of death was ischemic brain injury (n = 17). Twenty-four (30%) patients had a favorable outcome. Median duration of cardiopulmonary resuscitation for patients with favorable versus unfavorable outcome was 46 minutes (range: 14-95; interquartile range: 29-55) versus 41 minutes (range: 19-110; interquartile range: 30-55), P = .916. According to the logistic regression model, none of the following factors was a significant predictor of favorable outcome: age, weight, sex, etiology (cardiac vs noncardiac), duration of cardiopulmonary resuscitation, cannulation site, timing, or location of extracorporeal membrane oxygenation institution. CONCLUSIONS: Acceptable survival and neurologic outcomes (30%) can be achieved with extracorporeal cardiopulmonary resuscitation in children after prolonged cardiac arrest (up to 95 minutes) refractory to conventional resuscitation measures. Heart transplantation is often needed for successful extracorporeal cardiopulmonary resuscitation exit strategy. Lack of predictors of poor outcome support aggressive attempts to initiate extracorporeal cardiopulmonary resuscitation in all patients, followed by subsequent assessment of organ salvage.